Everyone knows about the “butterfly effect”: the idea that a butterfly flapping its wings in Brazil could eventually result in the formation of a tornado in Texas by virtue of very small alterations in the initial conditions of a system. Though this description of it is often decried by people who study chaos theory as an inaccurate oversimplification, it’s a useful illustration of the tiny perturbations that can have vast effects on a downstream chain of reactions.

When it comes to infectious diseases, climate change may be the beginning, but environmental effects extend much farther than just the weather. And while they may not be affected by the movement of a butterfly, even small environmental changes can mean large effects when it comes to microbiology. At a session Tuesday on Environmental Change and Disease, virologist Stephen Morse noted that “…environmental changes have always been associated with the appearance of new diseases, or the arrival of old diseases in new places. With more changes, we can expect more surprises.” I’ve mentioned this previously here, describing reasons why diseases “emerge”; the session today went much further, discussing infectious disease in terms of ecology, and how environmental changes have the capacity to alter much more than just our landscapes. More after the jump.

Like climate change itself, what will happen with infectious diseases in the context of an altered climate is very difficult to predict. For instance, increased rainfall may bring malaria to one place, creating small pools of water in which the mosquito vector can breed. In another area that already receives a lot of rainfall, additional precipitation could have the opposite effect, washing away larvae and decreasing malarial vectors in the region. And though this may not seem like it has relevance to the United States, recall that malaria used to be endemic here as well, and potentially could be again.

Additionally, many endemic diseases are susceptible to environmental change. West Nile, for instance, has quickly spread across the United States, while remaining more of a focused and local problem in areas of Europe. A reason is that the U.S. has many more species of mosquitoes which are able to act as vectors–species which are susceptible to changes in climate. The U.S. also currently enjoys a short influenza season in relation to tropical countries; could warmer temperatures cause influenza to be endemic year-round?

Terry Yates of the University of New Mexico highlighted another native example: hantavirus. The 1993 hantavirus outbreak occurred in part because of the El Nino events in the prior years. These created a bumper crop of pinyon nuts and other fruits and seeds, which in turn led to an increase in the rodent population. More rodents led to increased rodent population density, from less than one to 20-30 mice per hectare. This in turn put more humans in contact with hantavirus-contaminated rodent feces and urine, which led to an increase in hantavirus pulmonary syndrome. Researching the relationship between climate and hantavirus infections have even allowed Dr. Yates to create a sort of early warning system, noting conditions which are favorable for hantavirus infections.

Additionally, representatives from the World Health Organization have recently noted that changing climate could also have other health effects, including the spread of disease-carrying ticks into new areas and a longer pollen season.

Environmental change isn’t limited only to climate, either. Joan Rose of Michigan State University discussed environmental change that resulted from recent natural disasters: the 2004 Indonesia tsunami, and hurricanes Katrina and Rita in 2005. Both resulted in an increase in diarrheal diseases in the affected populations, including an outbreak of norovirus in New Orleans that sickened at least 1000. Rose notes, “Hurricanes, typhoons, and tornadoes have exacerbated an aging drinking and wastewater infrastructure, enhancing the mixing of untreated sewage and water supplies, re-suspended pathogens from sediments and displaced large populations to temporary shelters.”

While these are more direct effects of environmental change, Morse cautioned that indirect effects will be felt as well. This potentially includes an effect of global climate change on agriculture, which could in turn lead to changes in disease transmission and distribution. “If agriculture in a particular area begins to fail due to drought, more people will move into cities.” This could increase population densities and result in increased disease transmission, while potential food shortages due to drought could leave many in the population malnourished and immunocompromised.

Of course, this is a bleak scenario, but the speakers expressed optimism as well. Rita Colwell emphasized that this research into environmental effects on infectious disease “…represents shift from intense reductionism… to a holistic approach of infectious disease. Previously, we focused on the components of an organism that caused disease, and are shifting to understanding that environment plays a major role in epidemics.”

Colwell suggested that this shift provided us for the first time with a good ability to really predict, and hence prevent, infectious disease outbreaks; to carry out what she dubbed “pre-emptive medicine.” In contrast to the current approach where many researchers look for a “silver bullet” to fight a single disease (such as a drug or a vaccine), pre-emptive medicine would rely on predicting conditions conducive to massive epidemics, and determine when, where, and how intense they may be. “Then we could provide in a focused way the panoply of safe drinking water coupled with vaccine and medication, and target it effectively, rather than simply having shotgun approach. It provides us with a mechanism for addressing epidemics in strategic way, where we understand the complexity of the disease.”

Comments

There was also this paper published in PNAS last year which found that warmer springs and wetter summers in Asia could lead to an increase in the prevalence of bubonic plague. A one degree rise in spring temperatures is predicted to lead to a 50% increase in plague prevalence among its gerbil carriers.

I just finished my honours thesis on tabanids (deerflies and horseflies) in relation to forestry activity in Nova Scotia. It’s been fascinating reading some of the literature on this stuff.

But it’s also somewhat frightening how little data on basic life history there is available on some of these blood-feeding species. One of the problems I ran into was the lack of data available on differing habitat requirements between adult and larval life stages–what affects abundance at the adult stage is likely very different than what affects abundance at the larval stage!

Anyway… I wasn’t really studying any disease, and was more interested in fly ecology than anything. But talking about environmental change and vector-borne diseases was at least a good way to shut up any smarmy lab students that looked down on us “dirty ecologists” :p

A friend pointed this blog out to me. I happy to know I’m not the only one thinking along similar lines. Here’s some information about apergillosis and H5N1 from a non-scientist:

Aspergillosis, Aflatoxin and H5N1

* In Thailand in 2004, a young patient succumbed to infection by H5N1. (1)

* In December 2006, over 3,500 mallard ducks died along a small stretch of creek in Idaho – reported victims of infection by Aspergillus. (2)

* In June 2007, HPAI H5N1 began to be detected in migratory waterfowl in Western European countries at a time of year that is inconsistent with introduction via migrating waterfowl species. (3)

Is there a relationship between these seemingly distant and unrelated events? Could Aspergillosis infection be a co-factor for H5N1 infection in both migratory waterfowl and human beings? Could Aspergillosis infection be a factor in the mutation of LPAI avian influenzas into HPAI avian influenzas?

What is Aspergillosis?

Aspergillosis is a non-contagious respiratory tract infection caused by fungi of the genus Aspergillus. Aspergillus is a ubiquitous mold found in organic matter. In other words it is found everywhere, and it is only the health of our immune systems that prevent serious disease from being a common occurrence. In developed countries Aspergillosis is normally found in patients that have compromised immune systems such as transplant patients and patients suffering from disease such as leukemia and HIV-Aids. A. fumigatus is the primary species responsible for disease in wild birds and humans, but, there are more than 100 species of Aspergillus. Aspergillosis can be lethal.

Aspergillus in wild birds “…is not contagious, and it may be an acute, rapidly fatal disease, or a more chronic disease. Both forms of the disease are commonly seen in free ranging birds, but the acute form is generally responsible for large scale events for adult birds and for brooder pneumonia in hatching birds. Aspergillus sp. also produce aflatoxins but the significance of those toxins in the ability of the fungus to cause disease in birds is unknown… Chronic forms of Aspergillosis have been described in wild birds since at least 1813…” (4)

Aspergillosis in humans may cause many different diseases. These diseases may include a fungal invasion of the blood vessels in the heart, lungs and elsewhere, lesions in the lungs, and it may spread to the central nervous system (5). Symptoms may include fever, coughing up blood, consolidation in the lungs, and skin discoloration. (6)

Aspergillus and Aflatoxins

Aspergillus sp. also produce aflatoxins but the significance of those toxins in the ability of the fungus to cause disease in birds is unknown (4)

Aflatoxins are a serious environmental contaminant in developing countries where they cause thousands of deaths due to direct effects of the toxin, and unknown damage to health as a result of their immuno-suppressive effect.

“Aflatoxin contaminates such crops as corn, peanuts, rice, cotton, coconut, and cotton when they are improperly stored, especially in hot, humid climates. This highly toxic substance, produced by molds that exist in most environments, is one of the most carcinogenic compounds known and is a leading cause of liver cancer in developing countries; it can be absorbed by children through breast milk, thereby creating a lifelong exposure that can also contribute to malnutrition and a suppressed immune system. Studies have shown that, in most west African countries such as Ghana, approximately 95 percent of people show high levels of aflatoxin in their blood.”(

Aspergillus and Aflatoxins in Indonesia

Indonesia’s rubber production has a direct impact on the amount of aspergillus and aflatoxins in the environment. Rubber trees are frequently attacked by ‘white root disease’ which attacks the roots of mature trees and eventually kills them. As a defense against ‘white root disease’, farmers mix sulphur into the soil when the trees are planted. Sulphur is introduced because it encourages the growth and colonization of the roots by fungi that actually protect the roots from ‘white root disease’. Among the fungi that are colonized for this purpose are penicillium and aspergillus.

Most Indonesian rubber trees are grown on small holdings rather than agri-business plantations. It takes a number of years for a seedling to develop to the point where rubber latex can be harvested. For the interim, the government has promoted intercropping (planting other crops between the young trees) as a source of food and income for farmers until the trees mature. Of the major species of plants used for intercropping are several varieties of peanuts.

“Among the various raw and processed groundnuts collected from different points of the delivery chain (farmer, penebas, collector, processor and retailer) in Pati Regency, Central Java, Indonesia, the highest Aspergillus flavus infection and aflatoxin contamination were found in raw kernels of groundnuts collected from retailers in traditional markets. Post harvest handling methods prior to groundnuts being delivered to retailers and especially at the retailer level in traditional markets severely impact on the level of aflatoxin contamination in the Indonesian food chain…” (9)

Aspergillosis, Aflatoxins and H5N1 in Indonesia

There are a number of perplexing questions that have arisen from the data concerning H5N1 human infections in Indonesia. Among them are:

* H5N1 is endemic in poultry in Indonesia. There are hundreds of millions of poultry in Indonesia, and a very large number of them are raised in non-commercial, small holding scenarios, where the poultry also live in the household with humans. That being the case, why are their so few bird-to-human infections?

* The familial relationship of clusters where human-to-human transmission of H5N1 has been suspected or confirmed suggests a genetic component to the epidemiology of the disease. If such a genetic pre-disposition exists, must it involve H5N1 directly, or might it involve a genetic pre-disposition to Aspergillosis that makes H5N1 infection more likely for some than for others.

* A very high number of cases involve infants and toddlers. Could this be explained without reference to the famous ‘W-curve’ of the 1918 pandemic?

* A significant number of patients present with symptoms of respiratory distress and fever, are tested for H5N1 because of some involvement with poultry, and yet test negative for H5N1 infection and recover fully. Are these false negatives for H5N1 that are cured by Tamiflu treatment, or are they really something else that is cured by the antibiotics that are also administered early in the course of the disease when respiratory infection is suspected?

Discussion:

Aspergillosis and very high aflatoxin levels are endemic in West Africa (. Given the similarities between the market economies and agricultural practices in West Africa and Indonesia (and many other developing countries) is seems possible that Aspergillosis and aflatoxin levels are also very high in Indonesia. This could offer an explanation for two common, and I believe related scenarios:

Scenario 1 – Multiple chickens owned by a family die suddenly. One or more members of the family develope the ‘hot high’ and other ‘flu-like’ symptoms. But, most of the time only one of the family members test positive for H5N1 even though all of the family members are presumably exposed to the infected chickens because of their close proximity. The infected family member is frequently young, and often an infant or toddler.

Scenario 2 – There are a high number of pneumonias of unknown origin in Indonesia (and throughout the developing world). Also, it is common for patients that are subsequently found to be suffering from H5N1 infection do not come to the attention of government and health care professionals dedicated to H5N1 until they have been ill for several days. It is possible that patients presenting with “flu-like” symptoms (similar to symptoms of Aspergillosis) are initially given broad spectrum antibiotics. Most of these patients recover and never come to the attention of the medical community with regard to H5N1. And, the poultry connection is not investigated, nor is any diagnosis offered. (It is worth noting here, that Aspergillosis is rarely diagnosed except via postmortem examination)

However, after several days with no improvement a viral cause is suspected, and the poultry connection is investigated and testing for H5N1 begins. If the patient is H5N1 positive it is possible that Aspergillosis as a contributing factor is never pursued.

It is possible that an entire family is suffering from chronic Aspergillosis and related high levels of aflatoxins, and consequent immune system suppression, due to the prevalence of the aspergillus fungus in the environment (via poultry) and the food chain (nuts and grains bought in local markets). It is also possible that even though all family members are exposed to Aspergillosis, the youngest family members receive higher exposure because of close proximity to the floor and are ingesting aflatoxins through breast milk.

Finally, the small but finite possibility exists that only some family members are genetically pre-disposed to Chronic Granulomatous Disease mentioned above, making them more susceptible to respiratory infections in general, H5N1 in particular. That disposition could be genetically transmitted to offspring via the mother.

Chronic Aspergillosis and immune suppression may provide a sufficient explanation, as a co-factor, for the phenomena we see in human H5N1 infection in Indonesia, but without further research it cannot be determined if they are a necessary cause. AS I stated earlier, Aspergillosis is rarely diagnosed except by autopsy which is rarely accomplished in Indonesia for religious reasons.

However, given the similarities between migratory waterfowl and humans with reference to Aspergillosis and avian influenzas, perhaps migratory waterfowl could be studied to determine if Aspergillosis/aflatoxins are a co-factor for infection with avian influenzas.

Idaho and Western Europe

I made reference to the mallard duck die-off in Idaho and the diagnosis of Aspergillosis as the cause of death. I mentioned that, not because I suspect they really died from H5N1 infection, or that a cover-up occurred, but because they raise more related questions about a possible relationship between Aspergillosis and H5N1.

A convincing case has been made that LPAI H5N1 mutated into HPAI H5N1 as a result of commercial poultry practices. Furthermore, although we can easily distinguish the difference between LPAI and HPAI by looking at the cleavage site, we don’t know why the mutation occurs and therefore, we are concerned that it could occur in other circumstances.

Moreover, it appears that some species of migratory waterfowl can fly thousands of miles, and then die quite suddenly of HPAI H5N1 infection after they arrive at their destination. How does that happen? If we assume they are infected by HPAI during the entire journey then it is difficult to explain the delayed affect of the infection. Is it possible that these birds are also infected with Aspergillosis, and that the fungus, along with aflatoxin suppression of an immune system that is already suppressed by the stress of long distance flight, somehow enhances the ability of LPAI to mutate (or recombine) into HPAI. Is it possible that poultry infected with Aspergillosis and suffering immune suppression, including that caused by the stress of commercial poultry operations, suffer a similar fate?

There is a recent outbreak in detections of HPAI H5N1 in Western Europe. Dr. Niman is suggesting strongly that H5N1 is endemic in Western Europe since last year. I asked Dr. Niman why, if H5N1 has been endemic for a year, it is just showing up now. Dr. Niman replied sardonically that it could be a ‘Testing Outbreak’. But, he also suggested there may be a co-factor involved. I was curious about what such a co-factor could be, but it I let it go at that. Since then, I have not had time to see what the conditions in Western Europe are with regard to Aspergillosis. But, it has been demonstrated that environment changes such as drought can cause a dramatic increase in aspergillus spores in the environment because grain cracks under the influence of drought and allows the fungus to penetrate the grains and colonize more effectively than otherwise.

Conclusion:

The Idaho duck die-off occurred in December 2006. The outbreak in Western Europe is current. And, the situation in Indonesia has been on-going for quite some time. Why caused me to connect all these events now, and relate them to a young child who died in Thailand in 2004? In other words, what ‘clicked’ and instigated the research I have undertaken?

A couple of days ago I was re-reading old research articles, as I occasionally do, to see if I have previously missed something important. I was reading “”Influenza A Replication Sites In Humans” at the CDC site (1) when I came across this sentence describing the child’s lungs:

“Superimposed infection caused by fungus, morphologically consistent with Aspergillosis, was seen in some areas of the lung.”

(6) http://www.emedicine.com/med/topic174.htm
“…may cause a broad spectrum of disease in the human host, ranging from hypersensitivity reactions to direct angioinvasion. Aspergillus primarily affects the lungs, causing 4 main syndromes, including allergic bronchopulmonary aspergillosis (ABPA), chronic necrotizing Aspergillus pneumonia, aspergilloma, and invasive aspergillosis. However, in patients who are severely immunocompromised, Aspergillus may hematogenously disseminate beyond the lung, potentially causing endophthalmitis, endocarditis, and abscesses in the myocardium, kidney, liver, spleen, soft tissue, and bone. Aspergillus is second to Candida as a cause of fungal endocarditis. Aspergillus-related endocarditis and wound infections occur in the context of cardiac surgery…

Chronic necrotizing pulmonary aspergillosis (CNPA) is a subacute process usually found in patients with some degree of immunosuppression…

Chronic necrotizing Aspergillus pneumonia is rare. Frequently undetected in life and found at autopsy, the frequency of chronic necrotizing Aspergillus pneumonia may be underestimated…

In invasive aspergillosis and chronic Aspergillus pneumonia, the patient will be febrile (feverish) and may have evidence of lung consolidation. Patients may have hemoptysis (coughing up blood). Patients with invasive aspergillosis may be tachypneic (rapid breathing) and have rapidly progressive worsening hypoxemia (discoloration)…

Invasive aspergillosis is a rapidly progressive, often fatal infection that occurs in patients who are severely immunosuppressed, including those who are profoundly neutropenic (low white blood cell count), those who have received bone marrow transplant or solid organ transplants, and patients with advanced AIDS or chronic granulomatous disease(Chronic granulomatous disease (CGD) is actually a group of rare, inherited disorders of the immune system that are caused by defects in the immune system cells called phagocytes) . This infectious process is characterized by invasion of blood vessels, resulting in multifocal infiltrates, which are often wedge-shaped, pleural-based, and cavitary.